Contemporary research in cellular immunology has revealed that the nervous and the immune systems can influence each other in a variety of ways. The effect of opioids on defense mechanisms is of particular interest because drug addicts are prone to infectious diseases such as HIV-1, and morphine and its derivatives may serve as co-factors in spreading of these diseases. We have focused our interests on how macrophages are affected by opioids because these cells play a pivotal role in cellular defenses and in moderating the generation of antibodies. Opioids, including opioid peptides and opiates, have been reported to affect various macrophage functions such as phagocytosis and the oxidative burst. However, the literature in the area of opioid research is conflicted by the variety of model systems and experimental conditions used. Nevertheless two points are clear: l) the effects of opioids tend to be biphasic and are variably related to distinctive experimental conditions 2) opioid signal transduction in the nervous system involves elements similar to those involved in signal transduction by other chemical messengers; namely, receptors, G- proteins, ion channels and second messengers. We have demonstrated in our laboratory that morphine and other opioids can affect phagocytosis and NO production in murine macrophages. Furthermore, we have demonstrated that when these cells are exposed chronically to morphine, phagocytosis is no longer affected by this drug, suggesting that a state akin to desensitization or tolerance has been induced in vitro. We now wish to study these effects further by: l) a detailed pharmacological study, to determine if true morphine tolerance is developed in vitro in murine peritoneal macrophages. This study will also shed light on the opioid receptor involved in these effects. 2) repeating out observations on macrophages obtained from tolerant mice. This will enable us to determine if our previous results can be extrapolated to the in vivo situation 3) measuring changes in different elements of the signal transduction pathway under different conditions of opioid exposure. This work will contribute to understanding of opioid effects on cells of the immune system, including the underlying mechanism by which these effects take place.